Since the beginning of this project we have screened over 1200 subjects for this study. We have enrolled approximately 150 youth with bipolar disorder (BD), 140 subjects at risk for BD because they have a parent or sibling with the illness, and 100 adults with BD. This year, approximately 20 new subjects were enrolled. This year we continued our work designed to identify the brain mechanisms underlying BD in children;compare brain function in youth and adults with BD in order to begin to understand how the illness develops over time;and compare brain function in youth at familial risk for BD to those with BD and those at low risk, in order to facilitate the eventual development of preventive interventions. In terms of our work on the brain mechanisms mediating BD, much of that work consists of, not only comparing youth with BD to healthy youth, but also comparing youth with BD to those with severe, chronic irritability (the so-called severe mood dysregulation, or SMD, population, see MH002786-07). It is important to compare youth with BD and those with SMD because the latter frequently receive the diagnosis of BD in the community, despite not having a history of manic episodes. In work accepted for publication this year, we found that amygdala activity in youth with BD differed from that of youth with SMD and healthy youth when the subjects viewed angry faces. Further, in work being prepared for publication, we found that youth with BD differed from those with SMD and controls in the modulation of brain activity in response to increasing level of happiness on a face. Specifically, the groups differed in activity in face processing and attentional regions in response to happy faces. This may relate to the fact that the most distinctive clinical feature of BD is mania, which is characterized by euphoria and excessive reward-seeking. Overall, these studies identify specific deficits in brain function in BD that differentiate it from both normal function and from another population of youth with severe mood disorders. This year we made particular progress comparing brain function in adults and children with BD. Such studies are important because a current priority of the NIMH is to identify the developmental trajectory of BD, both clinically and in terms of brain function. To do this will require longitudinal studies of youth with BD that include both clinical assessment and repeated neuroimaging. Cross-sectional studies comparing brain function in adults and youth with BD provide important preliminary data to guide the approach of future longitudinal studies. In two studies that have been submitted for publication, we compared adults and children with BD on a face emotion processing task and a motor inhibition task. In both instances, we found similarities as well as differences in the deficits present in adults and youth with BD. On the face processing task, youth had amygdala dysfunction in response to a variety of facial emotions (angry, happy, fearful), whereas adults with BD differed from healthy subjects only in their response to fearful faces. Thus, on this task assessing function in a brain region that plays a central role in emotion regulation, both adults and children with BD showed deficits, but the deficits were more pronounced in youth. In addition, we compared adults and youth with BD on the brain mechanisms underlying motor inhibition. This psychological process is relevant to the symptoms of BD because patients in a manic state show severe impulsivity. On a motor inhibition task, both adults and youth with BD had dysfunction in striatal and ventral prefrontal areas, two brain regions that play a major role in motor inhibition. Interestingly, both adults and youth with BD showed dysfunction in the anterior cingulate cortex, a region that is important in cognitive control, but the direction of the dysfunction differed developmentally (hypoactivation in youth with BD, hyperactivation in adults with the illness). Thus, these data provide one example, in an important psychological process, of how the nature of brain dysfunction in BD may change over the course of the illness. As noted above, however, definitive conclusions about the developmental trajectory of BD cannot be made without longitudinal studies. Such studies are important in order to guide the development of age-appropriate treatment approaches and interventions to ameliorate the course of the illness. The cross-sectional studies completed this year provide data to guide those future studies. Our work in children at risk for bipolar disorder continues. In particular, this year we submitted for publication three papers that examine brain function in youth who are at risk for BD because they have a parent or sibling with the illness. This work stems from previous publications in which we demonstrated that such at risk youth share deficits on neuropsychological tasks with youth who have BD. For example, both youth with BD and those at risk for the illness have deficits labeling face emotion, and previous work by us and others demonstrates that youth with BD have abnormal amygdala activity when processing emotional faces. Extending this finding, in new work this year we found right amygdala hyperactivation in both at-risk youth without any psychiatric illness and BD subjects, compared to healthy subjects;BD and at-risk subjects did not differ from each other. This amygdala hyperactivation was present when subjects rated their fear of fearful faces. In our second study of youth at risk for BD, we examined brain function while subjects completed a cognitive flexibility task. In prior work, we had shown deficits on such tasks in youth with BD. We found a number of deficits that were shared by youth with BD and those who are at risk for BD but do not currently have psychiatric illness. Such deficits may represent heritable biomarkers, or endophenotypes, for BD. Specifically, we found that, during trials on which subjects were successful in completing the cognitive flexibility task, both BD and at risk youth had increased right ventrolateral prefrontal and inferior parietal activity, compared to healthy youth. Both regions are involved in mediating shifting attention during complex tasks, and considerable literature suggests that deficits in attention regulation may be present in relatives of patients with BD. During failed trials, both BD and at risk youth exhibited increased caudate activation relative to healthy youth, but BD youth showed increased activation in the subgenual anterior cingulate cortex relative to the other two groups. These data suggest that abnormal activity in ventrolateral prefrontal cortex, inferior parietal cortex, and striatum during a cognitive flexibility task may represent a potential BD endophenotype, but subgenual ACC dysfunction may represent a marker of BD illness itself. Finally, we examined the neural circuitry mediating motor inhibition in youth at risk for BD. Children at risk for BD engaged the left putamen during unsuccessful inhibition more than healthy comparison children. Youth with BD exhibited activation levels between these two groups but did not differ significantly from either one. This demonstrates that youth at risk for BD may show deficits in the neural circuitry mediating motor inhibition, even before they have symptoms of the illness.